1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 z Organic & Supramolecular Chemistry Cobalt-Copper Catalyzed C(sp2) – N Cross Coupling of Amides or Nitrogenated Heterocycles with Styrenyl or Aryl Halides Tubai Ghosh, Pintu Maity, and Brindaban C. Ranu* [a] An efficient C(sp2) – N cross coupling of cyclic and acyclic amides with styrenyl/aryl/heteroaryl halides catalyzed by cobalt acetylacetonate in combination with copper(I) iodide, has been achieved. A library of diversely substituted cyclic and acyclic enamides have been obtained in high yields by this procedure. The reaction is stereoselective producing (E)–enamides from trans-styrenyl halides and (Z)- products from cis-halides. This procedure has been successfully employed for the coupling of other N-heterocycles such as pyrazole, imidazole and triazole with aryl/styrenyl/heteroaryl halides to produce the corre- sponding N-coupled products. A probable mechanism has been suggested. Introduction The enamide moiety is an important substructure that is found in a wide range of natural products having biological activities [1] (Figure 1). Moreover, they form active constituent in many synthetic drugs. [2] They are also used as useful synthetic intermediates in various transformations. [3] Thus the synthesis of enamides is of much interest. The traditional method involved reaction of carbonyl compounds and amides. However this procedure required harsh conditions and produced mixture of E/Z isomers and the overall yield is also not good. [4] More efficient procedures such as metal mediated addition of amides to alkynes has been used for the stereoselective synthesis of enamides. [5] The metal mediated cross coupling reaction is an important tool and is used efficiently for carbon-carbon and carbon- heteroatom bond formation. [6] Recently, this protocol has been employed for the synthesis of enamides too. In fact, the amides are less reactive and thus coupling of amides is more challenging. Palladium has been used for the coupling of amides and aryl halides in the presence of a ligand, although this process has its limitations using costly palladium catalysts and ligand, and it also involves tedious purification of product. [7] Other less costly metals such as copper, [8] cobalt, [9] nickel [10] in the presence of ligands have also been employed. However, these procedures are also associated with drawbacks like reaction at high temperature for longer period, use of toxic and expensive ligands and limited substrate scope. Very recently, our group reported nickel-copper catalyzed coupling of cyclic and bridged amides with styrenyl/aryl halides in the absence of any ligand. [11] However, this method too has limitations with regard to reaction with electron withdrawing group substituted styrenyl/aryl halides, reaction with (Z)- styrenyl halides and primary aliphatic amides. This prompted us to find an improved method which can overcome these drawbacks. We discovered that cobalt(II) acetylacetonate in combination with copper(I) iodide is a right system to achieve this goal (Scheme 1). Results and Discussion To optimize the reaction conditions, a series of experiments were performed with variation of reaction parameters such as catalyst, base, solvent, temperature, and time for a representa- [a] T. Ghosh, P. Maity, B.C. Ranu Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India E-mail: ocbcr@iacs.res.in Homepage: http://www.iacs.res.in/ochem/ocbcr/ Supporting information for this article is available on the WWW under https://doi.org/10.1002/slct.201800575 Figure 1. Enamides containing natural products and biologically active molecules. Full Papers DOI: 10.1002/slct.201800575 4406 ChemistrySelect 2018, 3, 4406 – 4412  2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim